Process for producing granules

ABSTRACT

The invention relates to a process for the preparation of water-dispersible and water-soluble granules which exhibit superior properties in use while improving their ease and efficiency of manufacture. The process involves forming a particulate pre-mix of the components of the granule without forming a paste and extruding the pre-mix to form the granules.

This application is the National Phase of International ApplicationPCT/GB00/00163 filed Jan. 21, 2000 which designated the U.S. and thatInternational Application was published under PCT Article 21(2) inEnglish.

This invention relates to a process for the production of granules. Inparticular water dispersible and water soluble granules. Moreparticularly it relates to an extrusion process for the production ofwater dispersible granules. The invention is especially useful in theproduction of granules containing biologically active compounds andother substances and in particular, agrochemical products, for examplepesticides.

Dispersible granule formulations of pesticides are known and havecertain advantages. In particular, such granules are advantageous due totheir ease of handling and reduced worker exposure compared to powder orliquid formulations and also due to their compatibility, comparativecost. Furthermore, environmentally friendly packaging may be used andthe presence of inert materials also has environmental advantages. G. A.Bell, “Chemistry and Technology of Agrochemical Formulations”, Edited byD. A. Knowles (Kluver, 1998), pages 80-114, describes a range ofdispersible granule types and processes for their manufacture.

WO 89/00079 describes a process for the preparation of water dispersiblegranules which comprises mixing the desired ingredients of the granulesto form an extrudable wet mix which has a dough-like consistency, thatis, a consistency analogous to a stiff dough produced in the breadmaking process. Such dough-like consistency may be provided by thoroughmixing on kneading using a mixing apparatus such as a pug mill, doubleshafted auger, or an extrusion apparatus may be adapted to providesuitable mixing. It also requires that after extrusion the wetextrusions are broken down by rolling, preferably in a tumbling action.However, the rolling action required following extrusion may cause theformation of a “shell” of compacted material on the outside of thegranule that leads to an increase in the drying time/temperature.EP-A-00484 147 1 describes a process for preparing dispersible propanilgranules. Propanils is N-(3,4-dichloropheny)propionamide. It is knownthat propanil may degrade during processing or have poor stability dueto its low melting point. The process disclosed in EP-A-484 147comprises the steps in sequence of combining one or more surfactantswith propanil and milling to a particle size of less than 20 microns toform a premix, adding less than 25 percent by weight water andoptionally a wetting agent to said premix and mixing until a paste isobtained granulating said paste thereby producing granules and dryingsaid granules. This process is said to overcome certain difficulties inthe processing of propanil due to its low melting point and tendency tobecome sticky during processing.

However, propanil, in addition to having a relatively low melting point,is also prone to hydrolysis. The formation of a paste containing watermay lead to further difficulties as regards stability during processingif the energy input during the paste formation is too high. Thus, theabove described processes may impose a number of constraints on theingredients by limiting the choice of available components to thosewhich are not heat sensitive which may be included in the granules dueto the physical or chemical nature of those ingredients. In particular,the energy input required in the formation of the dough or paste maydegrade certain low-melting, or temperature-sensitive, active materials.Water-soluble or slightly-soluble actives may form crystal bridgeswhich, on addition to water, inhibit the rapid and desirably completedissolution or disintegration of the granules to their primary particlesize prior to granulation.

The handling of a dough or paste in a manufacturing plant can also causeprocessing problems. In particular difficulties may arise due tovariation in the viscosity of the dough or paste caused by temperatureand/or shear conditions. This factor may lead to variation in productquality and yield and may cause fouling or blockages in the processapparatus.

There remains a need for improvements to existing known processes ofpreparing granules that are dispersible and/or soluble in water to allowsensitive components to be included in formulations and to avoid orreduced processing problems for example due to fouling or blockage.Furthermore, granules providing excellent delivery of the active to thepoint of use including good dispersibility are desired. In additionphysical properties such as ease of handling, low friability so as toreduce or minimise the dust content are also desirable for reasons ofhealth and safety and ease of product distribution.

It has been found that acceptable granules may be produced by a processinvolving forming a pre-mix of the components of the granule andextruding the pre-mix provided that a paste is not formed during thepreparation of the pre-mix which is to be extruded.

In a first aspect the invention provides a process for the production ofwater dispersible granules comprising, preparing a pre-mix in the formof a free-flowing powder, preferably a homogeneous powder, comprising anactive material and an excipient and optionally other components, withat least one component of the pre-mix being liquid without forming apaste, and extruding the pre-mix in an extruder, for example a lowpressure extruder to form the granules. The excipient may be liquid inwhich case an additional liquid components is not required although afurther liquid component may be included as desired.

WO 96/25828 describes an apparatus and a method for extrusion whicheliminates the undesirable effect of the ingress of pastes, which formas the moist finely divided, water-insoluble powders are forced throughthe screen of conventional, low-pressure extruders.

It has been surprisingly found that granules that are water-dispersibleand/or water-soluble can be produced using the process according to theinvention and they provide excellent delivery of the active to the cropto be treated. Further, the granules produced by a process according tothis invention, exhibit improved characteristics as compared to granulesformed by process of the prior art on storage, dilution and in use.

The process involves the initial preparation of a pre-mix comprising theactive material together with at least one excipient in the form of afree-flowing, powder. Desirably the premix is a homogeneous powder. Thepre-mix is preferably prepared by the absorption of a liquid for examplewater, or any other suitable liquid onto an active solid material, whichis preferably finely divided. The active solid may be mixed with anexcipient preferably a surfactant for example a dispersant and a wettingagent, a filter, a disintegrant, a stabiliser, a flow aid and thelikeand mixtures thereof. It is especially preferred that the pre-mixcomprises an active, an excipient comprising a dispersant and water. Itis also preferred that the granule obtained from the process containsthese components. In a preferred embodiment, the active materials issuitably milled either prior to the addition of the excipient or milledtogether with it.

Suitably the premix is formed by the application of shear especially ina blending step or a milling step and optimally in one or more blendingsteps and one or more milling steps. Suitable apparatus for the blendingstep(s) include a low-shear, high intensity blender such as a LodigePloughshare mixer ribbon. Y-cone, double cone or trough blender, so thata free-flowing powder is formed. The premix is fed directly orindirectly into a suitable low-pressure extruder, such as that describedin WO 96/26828, so that the premix is compacted against the apertures inthe screen and forced through. The composition of the premix and theextruder settings are such that the formation of a paste beforeextrusion is avoided. The powder premix which is fed to an extruder isconverted into a compacted solid extrudate which can be collected as afree-flowing granule.

In the present process the material being processed remains a freeflowing particulate material during the formulation of the pre-mix. Inparticular, the material does not form a paste prior to extrusion.However, as the composition contains one or more liquid components, itmay be wet or dry provided that it remains free-flowing and particulateduring the process. The particles of the material are of such acomposition that they are able to move relative to one another and donot to any significant extent, agglomerate into lumps and remain aslumps having a particle size of at least several times that of the bulkof the particulate material being processed during the formation of thepre-mix. If any lumps are formed during this part of the process, theprocess conditions for formation of the premix and/or the composition ofthe premix should be varied so that the lumps disintegrate into finerparticles on application of shear. If any such lumps or agglomerates areformed, it is especially preferred that the agglomerate is of such acomposition and physical structure that it disintegrates into finerparticles on the application of manual force by rubbing between thefingers.

In the context of the present invention, a paste may be considered as amass of material, for example an agglomerate, which contains sufficientliquid or is at such a temperature that the particulate material beingprocessed forms into an agglomerate which is mouldable or deformable andwhich is not free-flowing. Thus, a paste does not disintegrate intofiner particles on application of shear, for example by rubbing betweenfingers, but rather remains as an agglomerated mass and the shear actsto mould or deform the agglomerate.

Depending on the components selected for producing the granules, therelative amounts of those components are selected and the processconditions for example the level of shear are selected so as to avoidthe formation of a paste prior to extrusion.

After the extrusion step in the process, the granules so formed may beprocessed further as desired, for example by drying and by sewing orother size-classification steps. In a preferred embodiment of theinvention, the granules are dried. The granules may be dried by anysuitable equipment, for example, a fluid-bed drier and a tray dryer. Asa further preferred process step, the granules are classified by size,for example, sieved so as to remove under- and over-sized material. In apreferred embodiment, the extruded material is suitably dried andsize-classified. It is especially preferred that the process of thepresent invention does not involve a rolling process step in which theextruded material is treated.

In the process of the present invention, uniform, free-flowing granulesare produced with excellent properties including uniform bulk density,lack of dust, resistance to attrition and rapid disintegration in waterto form a suspension or solution of the active ingredient on use. In apreferred embodiment, over 90%, especially 99% of the granules, prior tosieving or screening, are of a suitable size such that furtherprocessing to alter the size of the granules is not required.

Avoiding the formation of a paste during the process prior to extrusionaffords further advantages in that flexibility in the range of activesand other components which may be selected is increased as compared toprocesses in which a paste is formed. This permits the selection ofactives and other ingredients which otherwise may not be suitable due toincreasing processing difficulties. Thus any detrimental effects due tothe formation of a paste on the ingredients, and vice-versa, are nolonger a factor. Ingredients can thus be chosen that produce optimumproduct properties whether in use or otherwise, for instance indistribution, rather than the choice being compromised due to processingconsiderations.

The premix is suitably prepared by blending two or more materials, forexample the active and the excipient and/or the liquid component, for aperiod of at least 30 seconds, preferably 1 to 15 minutes, morepreferably 1 to 10 minutes and especially 2 to 5 minutes.

The solid component may be milled to an appropriate particle size priorto blending with other components. Preferably, milling is carried outafter blending so the blended materials are milled to a desired particlesize. Milling may be carried out by any suitable means although airmilling is preferred. Suitably air milling is carried out at an airpressure of at least 2 bar and desirably at least 5 bar. Suitably, themilled material has a particle size of 2 to 30 microns and desirably 4to 20 microns.

As desired one or more blending steps may be carried out after themilling step if desired. Such a blending step may be carried out for aleast 30 seconds, preferably for 1 to 15 minutes and especially for 1 to10 minutes. The one or more blending step may be carried out under lowshear or desirably high shear conditions. Where more than one blendingstep is employed, it is preferred that the material being processed issubjected to high shear in the first blending step and low or moderateshear in a subsequent blending step.

The liquid component may be added to the milled material, either a blendor a single component product, or it may be added to a solid componentin a blending step prior to or after the milling step. The liquid may beadded in any suitable manner although it is preferred that the liquid beadded as a spray in order to reduce the risk of agglomerates or lumpsforming in the premix.

It is essential in the formation of the pre-mix that the steps in theformation are carried out under such conditions are for a period suchthat a paste is not formed.

The process may be employed to produce granules comprising a wide rangeof active ingredients. By way of example, the process of the inventionmay be employed to produce granules comprising, as the active, apharmaceutical, an agricultural chemical, an oil field chemical, ananimal feedstuff, a dyestuff, and a detergent. Granules comprising othertypes of active may also be produced by a process according to theinvention. The process is particularly suitable for, but not limited to,the production of granules comprising an agricultural chemical.

Examples of agricultural chemicals which may be employed as the activeinclude abamectin, imidazolinone, ametryn, attrazine, azoxystrobin,benomyl, bensulfuron-methyl, bentzone, bifenox, bromoxynil, captan,carbendazim, carfentrazone-ethyl, chloridazon, chlorothalonil,chlortoluron, chlorsulfuron, cinosulfuron, clodinafop, clopyralid,lambda-cyhalothrin, cyhexatin, cymoxynil, alpha-cypermethrin,deltamethrin, difluofenican, diflufican, dimethormorph, diuron,ethofumesate, emamectin benzoate, fibronil, glyphosate,imazamethabenz-methyl, imazapyr, imazethapyr, imadacloprid, isoproturon,linuron, mancozeb, maneb, metamitron, methiocarb, metribuzin,metasulfuron-methyl, milbectin, nicosulfuron, oxadixyl, oxyfluorfen,phenmedipham, pirimisulfuron-methyl, propanil, propyzamide, rimsulfuron,simzaine, sulfometuron,-methyl, thifensulfuron-methyl, thiram,tribenuron-methyl, and triflusulfuron-methyl.

Suitable excipients include surface active agents (surfactants)including wetting agents and dispersing agents or a combination of bothand flow agents.

Examples of suitable wetting agents include: alkali metal, for examplesodium salts of alkyl aryl sulphonates, alkyl aryl sulphosuccinates, andalkyl sulphates.

Examples of dispersing agents include sodium lignosulphonates,sodiumnaphthalene sulphonate formaldehyde condensates, tristyrylphenolethoxylate phosphate esters, aliphatic alcohol ethoxylates, alkylphenolethoxylates, copolymers, random and block of ethylene oxide andpropylene oxide, “comb” graft copolymers are polyvinyl alcohol-vinylacetate coplymers.

Suitable other excipients include disintegrants for example: Bentonite,modified starch and polyvinyl pyrrolidone:stabilisers, for examplecitric acid, polyethylene glycol and butylated hydroxy toluene; andfillers, for example, starch, lactose, china clay, sucrose and kaolin.

In addition to the active material and the excipient and liquidcomponent, further ingredients, for example further excipients, may befed to the process at any point, including before, during or afteraddition of the liquid component to the process, just prior to or duringthe extrusion step. However, if further ingredients are to be added, itis especially preferred that they be added to the process prior toextrusion and optimally be mixed with the active component prior to orwith the addition of the liquid component. Suitable further ingredientsinclude surfactants including dispersants and wetting agents, fillers,disintegrants, stabilisers and flow-aids. The important factor in thechoice of a further ingredient and the amount of the ingredient is thatit does not lead to the formation of a dough or paste during the processfor example due to significant particle-to-particle interaction.

In an especially preferred embodiment of the invention, the activecomprises propanil and the excipients comprise one or more of adisintegrant, a flow agent a filler and a surfactant. In a furtherpreferred embodiment, the propanil is mixed with the disintegrant andflow agent, preferably by air milling, surfactant is then added to themixture and then water is added to the mixture so as to form afree-flowing generally homogeneous powder, that is a particulatematerial. In an alternative embodiment, the propanil is blended with asurfactant, a disintegrant and a filter and then milled and water isadded to the mixture after milling in a further blending step to producea free-flowing generally homogeneous powder. The pre-mix powder is thenextruded by passing through an extruder, preferably an extruder andextrusion process as described in WO 96/26828. The granules resultingfrom the extrusion process suitably have a thickness or particle size of0.1 to 5 mm, preferably 0.3 to 2 mm and especially 0.5 to 1.5 mm. Thegranules are then suitably dried and optionally classified by sieving.

The invention provides a novel granular composition comprising anagricultural active and an excipient obtainable by a process accordingto the first aspect of the invention.

The invention is illustrated by the following examples but is in no waylimited by them:

EXAMPLE 1

The following formulation was prepared:

Propanil 80% Sodium alkyl aryl sulphonate 1.0% Sodium Lignosulphonate10.0% Potato Starch 1.0% China Clay to 100%

The above formulation was prepared by first blending the PropanilTechnical, china clay and starch in a Ploughshare blender for 5 minutes.The blend thus formed was then air milled to an average particle size of5-7 microns. Water was added to the air milled premix in a Ploughshareblender until a water content of approx. 18% was obtained. Formation ofa paste was avoided in preparing the premix. The free-flowing powderobtained was fed to a basket extruder. A low pressure extruder as setout in WO-A-96/26828 was used to extrude the premix. A compacted solidextrudate was obtained, which was dried at 65° C. for 15 minutes until amoisture content of below 1.5% was obtained.

The granules were tested as follows:

1 g of the granules were added to a measuring cylinder containing 100mls of water. The cylinder was inverted through 180 degrees and backagain for one full inversion, taking 2 seconds and the number of secondsfor complete disintegration observed. The cylinder was then allowed tostand for 30 minutes, undisturbed, and a 10 ml sample taken from thecentre of the cylinder and analysed, gravimetrically, for the amount ofsolids present. This figure was then used to calculate the % of materialin suspension after standing for this time. The results were compared totwo commercial formulations of Propanil, one (STAM® 80 EDF) manufacturedby a standard extrusion technique involving the formulation of a pasteand the other (WHAM® 80DF) by pan granulation. The results obtained wereas follows:

Time Taken for % Remaining in Product to Suspension after 30 CommercialProduct Disintegrate minutes Stam ® 80 EDF 3-5 minutes 71.3 Wham ® 80DF >5 minutes 8.9 Example 1 1 minute 86.9

The above results indicate the advantages of the product produced by theprocess described in this invention. In addition it was noted that thestandard extruded product, Stam® 80 EDF was badly caked in thecommercial pack, indicating a physical degradation of the product onstorage.

EXAMPLE 2

The following formulation was prepared:

Chlorsulfuron 75% Sodium alkyl aryl sulphonate 1% Sodium lignosulphonate12.5% China Clay to 100%

The above formulation was prepared by first blending the ChlorsulfuronTechnical and china clay in a Ploughshare blender for 5 minutes. Theblend thus formed was then air milled to an average particle size of 3-4microns. Water was added to the air milled premix in a Ploughshareblender until a water content of approx. 14.5% was obtained. Formationof a paste was avoided. The free-flowing powder was extruded in anextruder as described in WO96/26828. A compacted solid extrudate wasobtained, which was dried at 60° C. for 15 minutes until a moisturecontent of 0.9% was obtained. The granules were tested by the method setout in Example 1.

The results were compared to a commercial formulation of chlorsulfuron,(GLEAN® 75 DF) manufactured by a standard fluid be agglomeration. Theresults obtained were as follows:

Time Taken for % Remaining in Product to Suspension after 30 CommercialProduct Disintegrate minutes Glean ® 75 DF <1 minute 69 Example 2 <1minute 86

It was noted that the Glean® sample was much more dusty than theextruded sample produced by the process of the present invention. At thelow use rate of the product, the higher susceptibility for the productwould lead to a higher availability in field use and a higher efficacy.

The results were compared to a commercial formulation of chlorsulfuron.(GLEAN® 75 DF) manufactured by a standard fluid bed agglomeration. Theresults obtained were as follows:

Time Taken for % Remaining in Product to Suspension after 30 CommercialProduct Disintegrate minutes Glean ® 75 DF <1 minute 69 Example 2 <1minute 86

It was noted that the Glean® sample was much more dusty than theextruded sample produced by the process of the present invention. At thelow use rate of the product, the higher susceptibility for the productwould lead to a higher availability in field use and a higher efficacy.

EXAMPLE 3

A commercial premix of Chloridazon 65 DF was obtained from which acommercial sample of water dispersible granule had been produced by awet agglomeration technique.

The same premix was formed into granules using the process of thepresent invention and both samples were tested for suspensibility as setout in Example 1. The results obtained are as follows:

% Suspensibility Commercial Chloridazon 65 DF 89 Example 3 98

EXAMPLE 4

The following formulation was prepared by a process according to thepresent invention:

Captan 80.0% Sodium alkyl aryl sulphonate 1.0% Sodium naphthaleneformaldehyde condensate 2.0% Silica 3.0% Kaolin to 100%

Zeta Potential Measurements may be used to evaluate themicro-electrophoretic mobility of active ingredient particles andaccordingly derive the Zeta Potential of those particles. This allowspreferred surfactants, in particular anionic, non-ionic and cationicdispersants, for water dispersible granules of the active ingredient tobe selected so as to identify the most appropriate candidatedispersants. It is preferred that the dispersants give a Zeta Potentialmeasurement of about 0 mV for a non-ionic surfactant and in excess ofapproximately −30 mV for an anionic surfactant and in excess ofapproximately +30 mV for a cationic surfactant.

The active material is suitably present at a level of at least 50%,preferably from 60 to 90% by weight of the granule. The excipient issuitably present at a level of less than 50%, preferably from 10 to 30%by weight of the granule. The liquid, preferably water, content of thegranule is suitably less than 10% and preferably from 0.1 to 5% byweight of the granule.

1. A process for the production of water dispersible granulescomprising, preparing a pre-mix in the form of a free-flowing powdercomprising an active material and an excipient with at least onecomponent of the pre-mixing being liquid, without forming a paste,feeding the pre-mix as a free-flowing powder to an extruder andextruding the pre-mix to form the water dispersible granules.
 2. Aprocess according to claim 1 in which a liquid is adsorbed onto anactive solid material.
 3. A process according to any one of thepreceding claims in which the pre-mix is a homogeneous powder.
 4. Aprocess according to claim 1 in which the premix is formed by theapplication of shear.
 5. A process according to claim 1 in which thepre-mix comprises an active material and an excipient selected from asurfactant, a filler, a disintegrant, a stabiliser, a flow aid andmixtures thereof.
 6. A process according to claim 1 which comprises apreparing the pre-mix in a blending step and optionally in a millingstep.
 7. A process according to claim 6 in which the blending step iscarried out for a period of at least 30 seconds.
 8. A process accordingto claim 7 which comprises feeding the active material to a blendingstep, passing the blended material to a milling step so as to reduce theparticle size of the blended material and passing the milled material toa further blending step to produce the pre-mix.
 9. A process accordingto claim 8 in which the first blending step is conducted underconditions of high shear and the second blending step is conducted underconditions of low or moderate shear.
 10. A process according to claim 9in which the active material and an excipient selected from adisintegrant, a filler and a surfactant and mixtures thereof are blendedin a blending step.
 11. A process according to claim 10 in which aliquid and optionally a further excipient selected from a surfactant, adisintegrant and a filler are added to the process in a second orsubsequent blending step.
 12. A process according to claim 1 in whichthe liquid is added as a spray.
 13. A process according to claim 1 whichfurther comprises drying and optionally size classifying the extrudedmaterial.
 14. A process according to claim 1 in which the activematerial is selected from, a pharmaceutical, an agricultural chemical,an oil field chemical, an animal feedstuff, a dyestuff, and a detergent.15. A process according to claim 1 in which the active material is anagricultural chemical and is selected from, bensulfuron-methyl, captan,chloridazon, chlorsulfuron, glyphosate, oxyfluorfen and propanil.
 16. Aprocess according to claim 1 in which the pre-mix comprises a surfactantselected from alkyl aryl sulphonates, alkyl aryl sulphosuccinates, alkylsulphates and lignosulphonates.
 17. A process according to claim 1 inwhich the granule comprises propanil and excipients comprising an alkylaryl sulphonate, a lignosulphonate, a disintegrant and a filter.